CDKN2B (p15INK4B) is a cyclin-dependent kinase inhibitor that functions as a potent suppressor of cell cycle progression through strong interaction with CDK4 and CDK6, inhibiting G1/S transition 1. The protein serves as a key effector of TGF-β-induced cell cycle arrest and cellular senescence 1. Transcriptional regulation of CDKN2B is complex; STAT3 hyperacetylation activates CDKN2B expression, contributing to cardiomyocyte senescence during aging 1, while PRMT5 and EZH2 cooperatively repress CDKN2B expression in colorectal cancer through epigenetic mechanisms including histone methylation and CpG methylation 2. Clinically, CDKN2B loss via 9p21.3 deletions represents a major oncogenic hallmark in acute lymphoblastic leukemia 3. Genetic variants in CDKN2B and its antisense RNA CDKN2B-AS1 associate with multiple diseases: CDKN2B-AS1 rs4977574 polymorphism correlates with coronary heart disease susceptibility, particularly in Asian populations 4, while CDKN2B rs1063192 polymorphism confers glaucoma protection 5. CDKN2B-AS1 functions as a long non-coding RNA involved in cancer progression and non-malignant conditions including cardiovascular disease, inflammation, and metabolic disorders 6. These findings establish CDKN2B as both a critical tumor suppressor and a therapeutic target across multiple disease contexts.